title: Metallomics for drug development: an integrated CE-ICP-MS and ICP-MS approach reveals the speciation changes for an investigational ruthenium(III) drug bound to holo-transferrin in simulated cancer cytosol.
abstract: A method based on combining inductively coupled plasma mass spectrometry (ICP-MS) with capillary electrophoresis (CE) or an ultrafiltration step was developed to study the speciation of the serum-protein adducts of a ruthenium anticancer drug under in vitro intracellular conditions. The formation of a reactive Ru species in the cell, following the metal release from the protein, is thought to play an important role in the drug's mode of action. Glutathione and ascorbic acid at their cancer cytosol concentrations were shown to be capable of altering the metal speciation in the drug adduct with holo-transferrin but not that with albumin. The appearance of the additional peaks in ICP-MS electropherograms (by recording both Ru- and Fe-specific signals) was found to be dependent on time which allowed for kinetic assessment of the evolution of novel metal species. On the contrary, after the addition of citric acid the ruthenium ion (within the appropriately complexed scaffold) remained sequestered in the adduct. This was inferred as a proof of the speciation changes taking place by a virtue of a redox mechanism rather than due to ligand-exchange transformations. The protein-bound metallodrug was further characterized by direct ICP-MS assaying so as to confirm a partial release of ruthenium induced by glutathione.
authors.affiliation: Vernadsky Institute of Geochemistry and Analytical Chemistry, Russian Academy of Sciences, Kosygin Str. 19, 119991 Moscow, Russian Federation.
authors.forename: Svetlana S
authors.initials: SS
authors.lastname: Aleksenko
authors.forename: Magdalena
authors.initials: M
authors.lastname: Matczuk
authors.forename: Xifeng
authors.initials: X
authors.lastname: Lu
authors.forename: Lidia S
authors.initials: LS
authors.lastname: Foteeva
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Pawlak
authors.forename: Andrei R
authors.initials: AR
authors.lastname: Timerbaev
authors.forename: Maciej
authors.initials: M
authors.lastname: Jarosz
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001205:Ascorbic Acid / Q000737:chemistry; D001798:Blood Proteins / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D019075:Electrophoresis, Capillary / Q000379:methods*; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry / Q000379:methods*; D009369:Neoplasms / Q000473:pathology; D010084:Oxidation-Reduction; D011485:Protein Binding; D012428:Ruthenium / Q000737:chemistry*; D013997:Time Factors; D014168:Transferrin / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D008024:Ligands; D014168:Transferrin; D012428:Ruthenium; D005978:Glutathione; D001205:Ascorbic Acid